Multitarget, Selective Compound Design Yields Potent Inhibitors of a Kinetoplastid Pteridine Reductase 1

• Type: Article in International Scientific Journal
• Date: 2022

Authors

Poehner, I (Author) Other; Quotadamo, A (Author) Other; Panecka Hofman, J (Author) Other; Luciani, R (Author) Other; Santucci, M (Author) Other; Linciano, P (Author) Other; Landi, G (Author) Other; Di Pisa, F (Author) Other; Dello Iacono, L (Author) Other; Pozzi, C (Author) Other; Mangani, S (Author) Other; Gul, S (Author) Other; Witt, G (Author) Other; Ellinger, B (Author) Other; Kuzikov, M (Author) Other; Santarem, N (Author) Other; Anabela Cordeiro da Silva (Author) FFUP; Costi, MP (Author) Other; Venturelli, A (Author) Other; Wade, RC (Author) Other

Journal

Title: Journal of Medicinal Chemistry

Vol. 65

Pages: 9011-9033

ISSN: 0022-2623

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 2 Citations

Scopus - 1 Citation

Other information

Authenticus ID: P-00W-WD5

DOI: 10.1021/acs.jmedchem.2c00232

Abstract (EN): The optimization of compounds with multiple targets is a difficult multidimensional problem in the drug discovery cycle. Here, we present a systematic, multidisciplinary approach to the development of selective antiparasitic compounds. Computational fragment-based design of novel pteridine deriva-tives along with iterations of crystallographic structure determi-nation allowed for the derivation of a structure-activity relation-ship for multitarget inhibition. The approach yielded compounds showing apparent picomolar inhibition of T. brucei pteridine reductase 1 (PTR1), nanomolar inhibition of L. major PTR1, and selective submicromolar inhibition of parasite dihydrofolate reductase (DHFR) versus human DHFR. Moreover, by combining design for polypharmacology with a property-based on-parasite optimization, we found three compounds that exhibited micromolar EC50 values against T. brucei brucei while retaining their target inhibition. Our results provide a basis for the further development of pteridine-based compounds, and we expect our multitarget approach to be generally applicable to the design and optimization of anti-infective agents.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 23